There is growing evidence that the host genetic make-up of an individual not only strongly influences risk of HIV-transmission and progression to AIDS but also plays a critical role in the development of specific AIDS defining illnesses such as HIV-associated dementia (HAD). In support of this hypothesis, we recently demonstrated that the GA/GA genotype for the monocyte chemoattractant protein 1 (MCP-1) gene is associated with a significantly increased risk of developing HAD [PNAS, 2002]. However, there are very few studies that have systematically determined the association between host genotype and development of HAD. In this collaborative study, we will test the following hypotheses: Aim # 1" will test the hypothesis that HAD is an inflammatory disease, specifically an encephalopathy perpetrated by secretory products of HIV-l-infected MPs. In this aim, we will investigate the genetic contribution of specific chemokines/cytokines/MMPs and TNFalpha in HAD pathogenesis. Aim #2 will test the hypothesis that the CXCR4-SDF axis that is thought to play a critical role in mediating neuronal dysfunction and apoptosis by the HIV-Env will alter risk of HAD. Aim #3 will test the hypothesis that there are common genetic-mechanistic links between Alzheimer's disease and HAD. There are two significant strengths of this proposal: First, to address directly the importance of the host genetic of HAD, we will capitalize on the largest cohort of HIV-1 seropositive individuals (1,132 subjects) followed at a single U.S. medical center. Several unique epidemiological features, including the large number of Caucasians and African-Americans in this cohort, provide us the power to study the effects of genetic polymorphisms in HAD. Second, we will use a combination of epidemiologic study designs tailored to address each specific aim. For example, we will use the nested case-control study, the case-cohort study in addition to the traditional cohort study to dissect out the population level effects of various genotypes. The research is significant because (1) it will use the powerful approach of genetics to address the mechanisms underlying what arguably is the most common cause of dementia in the world in individuals less than the age of 40, namely HAD; (2) it has the potential for establishing a broadly applicable paradigm for approaches to dissect the genetic basis for other complex, multi-etiologic disorders in which the products of a multiplicity of genes interact with each other and with environmental factors. For example, given the similarities in the inflammatory processes associated with HAD, autoimmune diseases such as multiple sclerosis, and degenerative diseases such as AD and Parkinson's disease, our findings may provide evidence of common etiologic factors or genetic networks that play a role in the pathogenesis of this diverse group of diseases. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HAD susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA) and epidemiology/virology statistics (NHMC). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46 110. We have submitted a request for addition of a new subtitle: "Genetic epidemiology of HIV-associated dementia". [unreadable] [unreadable] [unreadable]